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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王惠鈞(Andrew H.-J.Wang) | |
| dc.contributor.author | Chia-I Liu | en |
| dc.contributor.author | 劉佳宜 | zh_TW |
| dc.date.accessioned | 2021-06-08T05:04:05Z | - |
| dc.date.copyright | 2011-02-20 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-02-13 | |
| dc.identifier.citation | Akamine, S., Nakamori, K., Chechetka, S.A., Banba, M., Umehara, Y., Kouchi, H., Izui, K., and Hata, S. (2003). cDNA cloning, mRNA expression, and mutational analysis of the squalene synthase gene of Lotus japonicus. Biochim Biophys Acta 1626, 97-101.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23568 | - |
| dc.description.abstract | 鯊烯合成酶 (Squalene synthase , SQS)隸屬於異戊二烯轉移酵素(trans-Prenyl transferase) 在低等酵母菌與高等人類間極具保留性，利用其C碳末端依附於內質網膜上；而人類鯊烯合成酶更為催化膽固醇合成的首要關鍵步驟，可以此作為治療高血酯症的藥物標的物。該酵素縮合兩分子碳15焦磷酸酯（Farnesyl pyrophosphate, FPP）成一分子碳30碳氫化合物，也就是鯊烯 (Squalene)作為終產物，其中包含兩獨特步驟。首先，給予者焦磷酸酯(Donor FPP)要將雙磷酸基解離成碳正離子(carbocation)，插入於接受者焦磷酸酯(Acceptor FPP) 碳2-碳3雙鍵間，以形成碳1’-2-3 環化中間產物為前鯊烯雙磷酸 (Presqualene pyrophosphate, PSPP)。接著，前鯊烯雙磷酸之雙磷酸基會解離成環丙基代甲基陽離子(Cyclopropylcarbinyl cation)，並在依賴型菸草醯胺腺嘌呤二核苷酸磷酸鹽(NADPH-dependent)的結合下進行位向域選擇性(regioselective)與立體選擇性(stereoselective)之還原反應來得到鯊烯。在本研究中，我們取得雙端截短之人類鯊烯合成酶 (31-370) 蛋白質結構，以及其與受質類似物、環化中間物類似物、抑制劑之複合體蛋白質結構。得知該酵素全由α-螺旋所構成，且具兩彈性區域來調節受質、中間產物、輔因子之結合，而這些結構可用以定義人類鯊烯合成酶之受質與環化中間產物結合區。同時，我們觀察到被認為用來結合輔因子之第四區高度保留區，也形成另一空間；有趣的是，來自真菌代謝物之薩拉哥酸（Zaragozic Acid-A, ZA-A）為最重要鯊烯合成酶抑制劑之一，其碳-6醯基亦結合於此。基於人類鯊烯合成酶與金黃色葡萄球菌之前鯊烯合成酶(CrtM)具有結構相似性，故可將鯊烯合成酶抑制劑應用於CrtM以當作治療感染之藥物前驅物；儘管CrtM蛋白質序列不具第四區，但薩拉哥酸仍有效抑制CrtM活性。從CrtM電腦模擬、突變株測試、與CrtM突變株/薩拉哥酸複合體結構，提供可針對致病性金黃色葡萄球菌而不影響體內膽固醇之合成，來設計新型選擇性抑制劑的機會。 | zh_TW |
| dc.description.abstract | Squalene synthase (SQS) belonging to the trans-Prenyltransferase family is highly conserved in yeast and human, and it is an ER-associated enzyme by the C-terminal end. Human SQS catalyzes the first committed step in cholesterol biosynthesis and serves as an attractive target for hypercholesterolemia treatment. It condenses two molecules of C15 farnesyl pyrophosphate (FPP) to form a C30 hydrocarbon product, squalene. The hydrodrophobic metabolite formation reaction contains two unusual steps. The pyrophosphate group released first from the donor FPP, and then the carbocation inserted into the C2-C3 double bond of the acceptor FPP to generate the C1´-2,3 cyclopropylcarbinyl intermediate, presqualene pyrophosphate (PSPP). In the second step, as the other diphosphate group releases, the cyclopropylcarbinyl cation undergoes the rearrangement with NADPH-dependent regioselective and stereoselective reduction to gain squalene. In this study, we obtained the structures of the doubly truncated enzyme, human SQS (31-370), alone and complexed separately with substrate and intermediate analogues, and a potent inhibitor. Human SQS (31-370) folds into an all α-helical structure with two flexible regions for regulating substrate, intermediate, and cofactor binding. These structures defined the FPP, and PSPP binding sites in human SQS. It was further observed that the alternative cavity consists of conserved region IV, which was proposed as the cofactor binding site. Interestingly, the C-6 acyl group of zaragozic acid-A (ZA-A), one of the most potent SQS inhibitors identified from the fungal metabolite, occupies this region. Based on the structural similarities between human SQS and S. aureus dehydrosqualene synthase (CrtM), SQS inhibitors provide another important application against S. aureus CrtM as anti-infective prototype compounds. Although the CrtM protein sequence bears no homology to conserved region IV, ZA-A shows a low micromolar activity against CrtM. The inhibitor docking mode, mutagenesis assays, together with CrtM mutant/ZA-A structure, presents an opportunity to address the design of new selective inhibitors targeting pathogenic S. aureus without interfering de novo sterol biosynthesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T05:04:05Z (GMT). No. of bitstreams: 1 ntu-100-D94b46004-1.pdf: 18889480 bytes, checksum: e464409a0460dcf1a73053e6c6a43077 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 中文摘要(I)
Abstract (III) Abbreviations (V) Chapter 1 Introduction 1.1 Prenyltransferases (2) 1.1.1 “head-to-tail” trans-Prenyltransferases(7) 1.1.2 “head-to-head” trans-Prenyltransferases(8) 1.2 Human squalene synthase (SQS) (9) 1.2.1 The first half-reaction (16) 1.2.2 The second half-reaction (22) 1.2.3 The effect of magnesium on SQS activity (31) 1.3 Human SQS as a potential target for cholesterol-lowing drugs (31) 1.4 Zaragozic acids (ZAs) display low nM activity against SQS (34) 1.5 Study purpose (36) Chapter 2 Materials and Methods 2.1 Chemical (39) 2.2 Cloning of human SQS cDNA (31-370) and the construction of expression vector (39) 2.3 Protein expression and purification (39) 2.4 Crystal screening for human SQS (41) 2.5 Mutagenesis for human SQS (41) 2.6 ITC (Isothermal Titration Calorimetry) assay (41) 2.7 Data collection, structure determination and refinement 2.7.1 Data collection (42) 2.7.2 Structure determination and refinement (42) 2.8 Activity assay (43) Chapter 3 Results 3.1 Cloning and expression of human SQS (31-370) 3.1.1 Cloning of human SQS cDNA (45) 3.1.2 Expression using pET28a vector (45) 3.2 Screening for human SQS (31-370) crystals (46) 3.3 Crystal structure of human SQS (31-370) and of its complexes with substrate and intermediate analogues(46) 3.3.1 Human SQS presents a Mg2+-dependent enzyme(47) 3.3.2 Overall structure of human SQS (31-370)(47) 3.3.3 Structure of human SQS active site (48) 3.3.4 Structures of the human SQS (31-370)/substrate analogue (FsPP) complex with and without Mg2+ (51) 3.3.5 Structure of the human SQS (WT)/intermediate analogue (s-PSPP) complex(55) 3.3.6 Structure of the human SQS F288A/intermediate analogue (s-PSPP) complex (57) 3.4 Inhibition assay and the structural study of potent SQS inhibitor, Zaragozic acid A (ZA-A) 3.4.1 Binding affinity of ZA-A on human SQS (31-370) (58) 3.4.2 Structure of human SQS (31-370)/ZA-A complex (59) 3.5 ZA-A as a potent inhibitor against S. aureus CrtM 3.5.1 ZA-A shows low micromole activity against S. aureus CrtM (62) 3.5.2 Structural docking of ZA-A on S. aureus CrtM (63) 3.5.3 Binding affinity of ZA-A on S. aureus CrtM (64) 3.5.4 Structure of CrtM Y248A/ZA-A complex (65) Chapter 4 Discussion 4.1 Comparison of the active site structures between human SQS with S. aureus dehydrosqualen synthase (CrtM)(68) 4.2 The proposed catalytic mechanism of human SQS (69) 4.3 Further applications of drug designs on cholesterol-lowering agents and anti-infectives (74) Tables (76) Figures(80) References(108) Publications(115) | |
| dc.language.iso | en | |
| dc.title | 人類狡鯊烯合成酶結構與zaragozic acid A複合體：催化機制與藥物設計之方向 | zh_TW |
| dc.title | Structures of human squalene synthase and its complex with zaragozic acid A: Catalytic mechanism and implication in drug design | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 林俊宏(Chun-Hung Lin),蕭傳鐙(Chwan-Deng Hsiao),詹迺立(Nei-Li, Chan),馬徹(Che Ma) | |
| dc.subject.keyword | 鯊烯合成酶,薩拉哥酸, | zh_TW |
| dc.subject.keyword | Squalene synthase,Zaragozic Acid-A, | en |
| dc.relation.page | 115 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2011-02-14 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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